Compounds and methods for repelling blood-feeding arthropods and deterring their landing and feeding

ABSTRACT

This invention relates to a group of compounds for repelling blood-feeding ectoparasitic arthropods, and a method of deterring their landing and feeding on animals including humans, by applying in one or more formulations compounds that incorporate one or more sulfide and one or more hydroxyl groups to the skin, clothing or environment of animals, including humans. A method of repelling and deterring landing and feeding by blood-feeding arthropods on an animal by applying in effective amount one or more compounds that incorporate alkyl sulfide and alcohol moieties, or alkyl sulfide and amide moieties, or alkyl sulfide and amide moieties to the skin, clothing or environment of an animal.

FIELD OF THE INVENTION

This invention relates to a group of compounds for repelling blood-feeding ectoparasitic arthropods, and a method of deterring their landing and feeding on animals including humans, by applying in one or more formulations compounds that incorporate one or more sulfide and one or more hydroxyl groups to the skin, clothing or environment of animals, including humans. The invention further relates to a group of repellent and deterrent compounds that incorporate one or more sulfides and one or more amides.

BACKGROUND OF THE INVENTION

Haematophagous insects and certain other blood-feeding arthropods are ubiquitous ectoparasites of animals, including humans. In so doing, blood-feeding ectoparasitic arthropods constitute a major source of annoyance to humans and other animals, and are vectors of many microbial diseases, as well as those caused by viruses and virus-like disease agents (Harwood and James 1979).

Blood-feeding arthropods that annoy man and animals through their biting and feeding activity, and often vector disease-causing pathogens, comprise members of numerous insect taxa, including, but not limited to: flies in the Families Culicidae, Tabanidae, Psychodidae, Simuliidae, Muscidae and Ceratopgonidae (Order Diptera), bugs in the Families Cimicidae and Reduviidae (Order Hemiptera), lice in the Orders Mallophaga and Anoplura, and fleas in the Order Siphonaptera, as well as non-insectan arthropods, particularly ticks and mites in the Order Acari (also known as Acarina).

An example of a significant annoyance to humans and a major vector of disease-causing pathogens is the yellow fever mosquito, Aedes aegypti (Diptera: Culicidae), an exceptionally resilient blood-feeding species that breeds in any small container of water (Malavige et al. 2004). Adults are highly domesticated, typically resting indoors in dwellings, thus optimizing their opportunity to feed and vector pathogens that cause diseases such as yellow fever and dengue fever (Mackenzie et al. 2004; Malavige et al. 2004; Hill et al. 2005). Annually, 7.2 million humans become infected with yellow fever, and >30,000 die from the disease. Moreover, 50-100 million humans are infected with dengue fever (500,000 with its hemmorhagic form), resulting in approximately 24,000 deaths annually (Zanotto et al. 1996; Mairuhu et al. 2004). Other species of Aedes, as well as mosquitoes in other genera, particularly Anopheles and Culex, are also significant annoyance agents and vectors of disease-causing pathogens.

The most effective protection against mosquitoes and other ectoparasitic arthropods, is to repel them from, or deter their landing and feeding on, potential hosts. Until recently, the most efficacious known “repellent” was N,N-diethyl-m-toluamide (DEET) (Fradin and Day 2002). There are concerns associated with N,N-diethyl-m-toluamide. It is a solvent for some plastics, paints, varnishes and synthetic fabrics (Trigg 1996; Badolo et al. 2004; Miot et al. 2004). When used alone it may attract rather than repel A. aegypti. Finally, products exceeding 30% N,N-diethyl-m-toluamide are not recommended for protection of children (Pest Management Regulatory Agency 2002). Thus, there is a strong need for alternatives to N,N-diethyl-m-toluamide.

Research has led to several alternative repellents and deterrents to date, some of them with efficacy equal to that of N,N-diethyl-m-toluamide (Barnard and Xue 2004). Many of these are natural compositions, and include essential oils from plants (cedar, rosemary, eucalyptus, andiroba, catnip, thyme, neem, clove, soybean) and grease or oils from animals. Active ingredients in some of these oils have been isolated and formulated in commercial products. OFF!® botanicals, for example, contain p-menthane-3,8-diol from lemon eucalyptus, Eucalyptus maculata citriodon (Beldock et al. 1997; Carroll and Loye 2006) as the active ingredient. Other new repellents for mosquitoes and other arthropods that are found in natural sources include: 2-undecanone (methyl nonyl ketone) from tomato plants (Roe 2002, 2004, 2007; Roe et al. 2006); tetrahydronootkatone (1,4,4a,5,6,7,8,10-octahydro-6-isopropyl-4,4a-dimethyl-2(1H)-naphthalenone) and 1,10-dihydronootkatone (1,4,4a,5,6,7,8,10-octahydro-6-isopropenyl-4,4a-dimethyl-2(1H)-naphthalenone) from yellow cedar (Zhu et al. 2005); and callicarpenal (13,14,15,16-tetranor-3-cleroden-12-al) and intermedeol [(4S,5S,7R,10S)-eudesm-11-en-4-ol] from American beautyberry (Cantrell et al. 2005, 2006; Carroll et al. 2007).

Most recently, Gries et al. (2008) report analyses of odorants in garlic essential oil with the objectives to (i) understand the moiety(ies) of molecules that convey offensive smell and insect repellency and (ii) engineer odorless compounds with greater repellency than their natural counterparts. The invention by Gries et al. (2008) relates to compounds that incorporate one or more allyl sulfide, allyl disulfide, and/or allyl polysulfide moieties, and one or more hydroxyl groups, and are used to repel or deter landing and feeding of mosquitoes on humans. 8-Allylsulfanyloctan-1-ol was the key compound which by itself or in combination with an adjuvant was more effective than DEET in deterring biting by the mosquitoes Anopheles gambiae, Culex quinquefasciatus, and Aedes aegypti.

SUMMARY OF THE INVENTION

The invention is directed to a method of repelling and deterring landing and feeding by blood-feeding arthropods on an animal by applying in effective amount one or more compounds that incorporate alkyl sulfide and alcohol moieties, or alkyl sulfide and amide moieties, or allyl sulfide and amide moieties to the skin, clothing or environment of an animal.

Compounds that incorporate alkyl sulfide and alcohol moieties can be aliphatic primary, secondary or tertiary alcohols with alkylsulfide moiety.

Said blood-feeding arthropod repellent and deterrent compounds can be selected from the group including, but not limited to, the following: 8-methylsulfanyloctan-1-ol, 8-ethylsulfanyloctan-1-ol, 8-propylsulfanyloctan-1-ol, 8-butylsulfanyloctan-1-ol, 8-pentylsulfanyloctan-1-ol, (N,N)-diethyl-8-allylsulfanyl-octanamide.

Effective amounts of said compounds that incorporate alkyl sulfide and alcohol moieties, or alkyl sulfide and amide moieties, or allyl sulfide and amide moieties can be combined with one or more additional compounds applied in effective amount to improve the repellent and deterrent effect against landing and feeding by blood-feeding arthropods.

The blood-feeding arthropods can include, but are not limited to, ticks and mites in the Order Acari (also known as Acarina) and insects in the Orders Mallophaga, Anoplura, Siphonaptera, Hemiptera (Families Cimicidae and Reduviidae), and Diptera (Families Culicidae, Tabanidae, Psychodidae, Simuliidae, Muscidae and Ceratopogonidae).

The blood-feeding insects in the family Culicidae can include, but are not limited to, species in the genera Aedes, Culex, Anopheles, Chagasia, Bironella, Culiseta, Ochlerotatus, Psorophora, Toxorhynchites, Mansonia, and Coquillettidia. The insects can be Aedes aegypti, Anopheles gambiae and Culex quinquefasciatus.

The animal can be a mammal, bird, reptile or amphibian. The mammal can be a human. The environment of an animal may include, but not be limited to, bedding, furniture, dwellings and vehicles.

An effective amount of said blood-feeding arthropod repellent and deterrent compounds can range from 1 nanogram to 100 milligrams per square centimeter of skin, clothing or environmental substrate.

The blood-feeding arthropod repellent and deterrent compounds can be formulated in an effective amount with a carrier material for application to the skin, clothing or environment of an animal.

The invention is also directed to a composition for repelling and deterring landing and feeding by blood-feeding arthropods on an animal comprising an effective amount one or more compounds that incorporate alkyl sulfide and alcohol moieties, or alkyl sulfide and amide moieties, or allyl sulfide and amide moieties.

DESCRIPTION OF THE DRAWINGS

FIG. 1 illustrates synthetic pathways to (N,N)-diethyl-8-allylsulfanyl-octanamide (Scheme 1), 8-methylsulfanyl-1-octanol (Scheme 2), and 8-propylsufanyl-1-octanol (Scheme 3).

FIG. 2 shows the duration of protection of a 100 cm² area of an exposed human forearm from bites by Aedes aegypti caused by 10% formulations of either 8-methylsulfanyloctan-1-ol (experiment 1), 8-ethylsulfanyloctan-1-ol (experiment 2), 8-propylsulfanyloctan-1-ol (experiment 3), 8-butylsulfanyloctan-1-ol (experiment 4), 8-pentylsulfanyloctan-1-ol (experiment 5) or 8-allylsulfanyloctan-1-ol (experiment 6) in mineral oil applied to the skin at a dose of 1.5 mg per cm², as opposed to no protection provided by mineral oil alone.

FIG. 3 shows the duration of protection of a 100 cm² area of an exposed human forearm from bites by Aedes aegypti caused by 10% formulations of (N,N)-diethyl-8-allylsulfanyl-octanamide (experiment 7) or 8-allylsulfanyloctan-1-ol (experiment 6) in mineral oil applied to the skin at a dose of 1.5 mg per cm², as opposed to no protection provided by mineral oil alone.

DETAILED DESCRIPTION OF THE INVENTION

The inventors' own research (Gries et al. 2008) has shown that 9-allylsulfanylnonan-1-ol, 8-allylsulfanyloctan-2-ol, and 8-allylsulfanyloctan-1-ol are repellent to mosquitoes.

In this application, the inventors disclose the discovery of a new set of compounds, including 8-methylsulfanyloctan-1-ol, 8-ethylsulfanyloctan-1-ol, 8-propylsulfanyloctan-1-ol, 8-butylsulfanyloctan-1-ol, 8-pentylsulfanyloctan-1-ol and (N,N)-diethyl-8-allylsulfanyl-octanamide that among other insects are deterrent to mosquitoes.

FIG. 1 illustrates synthetic pathways to (N,N)-diethyl-8-allylsulfanyl-octanamide (Scheme 1), 8-methylsulfanyl-1-octanol (Scheme 2), and 8-propylsufanyl-1-octanol (Scheme 3).

Exanoke 1 Experimental Insects

A black-eyed Liverpool strain of Aedes. aegypti was obtained from Dr. Carl Lowenberger, Simon Fraser University (SFU). Insects were reared under standardized conditions (60-70% relative humidity, 26-28° C., 14 h light:10 h dark photoperiod) in SFU's insectary. Neonate larvae that hatched in glass dishes of sterilized hypoxic water were transferred to trays of distilled water provisioned with Nutrafin® Basix Staple Food fish diet. Pupae were collected daily and separated by sex, and 15 females and 10 males were placed in a paper cup (7.5 cm diameter, 8.5 cm high) with a mesh lid. Emergent adults were fed a 10% (w/v) sucrose solution via braided cotton dental rolls. Arm-fed gravid females were offered water-containing paper cups, lined with paper-towel as an oviposition substrate.

Example 2 General Bioassay Procedure

Candidate repellents and deterrents were bioassayed according to a modified protocol from the World Health Organization (1996). At least 1 hour prior to each bioassay, 75 host-seeking non blood-fed, nulliparous, 5- to 8-day-old female Aedes aegypti were placed into a wood-framed cage (26.5 cm on each side and 42.5 cm high) with a wooden floor, screened mesh sides and top, and a clear acrylic front fitted with a cotton stockinette sleeve (10 cm diameter). The test subject's arm was covered with an elbow-length polyethylene glove with an excised patch (16.6 cm long, 6 cm wide) to expose the ventral forearm of the test subject. Candidate deterrents were formulated in mineral (paraffin) oil and applied to the exposed forearm 5 min prior to inserting the arm into the cage. The inserted arm remained in the cage for 3 min every 30 min. Prior to each 3-min bioassay period, the hand of the untreated arm was inserted into the cage to ascertain that it received 10 bites within 30 sec as an indication of “biting pressure”.

The bioassay was terminated when the treated arm received ≧2 bites in one 3-min bioassay period or one bite in each of two consecutive bioassay periods. The time elapsed from experiment initiation to first bite was recorded as deterrent failure or complete protection time.

Example 3 Synthesis of (N,N)-Diethyl-8-allylsulfanyl-octanamide (FIG. 2, Scheme 1)

A mixture of allylbromide (1, 1.30 ml, 15 mmol) and thiourea (1.45 g, 15 mmol) was refluxed in 50 ml of anhydrous ethanol for 3 hours and cooled to 25° C. Pellets of KOH (1.62 g, 30 mmol) were added together with water (0.30 ml). The reaction mixture was then refluxed for 2 hours. 8-Bromooctanoic acid was alkylated with potassium allylmercaptade (Jie et al. 1989) by adding to the reaction mixture 8-bromooctanoic acid (2.23 g, 10 mmol) and KOH (1.30 g), and refluxing for 5 hours under argon. Thereafter, water (50 ml) was added and the reaction mixture was extracted with hexane (2×40 ml). The aqueous solution was acidified with conc. HCl and extracted again with ether (2×40 ml). Ethereal extracts were washed with a saturated aq. NaCl solution and were dried over anh. MgSO₄. Evaporation of solvents gave 8-allylsulfanyl-octanoic acid (2) (50% pure by GC); MS [m/z (rel. intensity)]: 216 (M+,100), 199 (26), 169 (20), 157 (37), 139 (18), 123 (19), 113 (49), 95(26), 87 (34), 74 (69), 55 (52), 45(62), 41 (69).

Without further purification, the crude acid was dissolved in dry benzene (50 ml), and freshly distilled thionyl chloride (1.50 ml) was added. The reaction mixture was warmed to 50° C. and stirred for 5 hours under argon. Excess thionyl chloride and benzene were removed in vacuo. The residue in 20 ml of ether was stirred at 0° C., and diethylamide (4 ml) was added slowly. After 20 min, water (10 ml) was added and the product was extracted (2×40 ml) with a 1:1 ether/hexane mixture. Extracts were washed with a saturated aq. NaCl solution, dried over anh. MgSO₄, concentrated and purified by flash chromatography, using ether/hexane mixtures with increasing proportions of ether (40, 50 and 70%) as consecutive eluents. The yield of (N,N)-diethyl-8-allylsulfanyl-octanamide (3)(75% pure by GC) was 0.87 g (24% yield); MS [m/z (rel. intensity)]: 272 (M+1, 74), 230 (100), 198 (44), 157 (20), 126 (24), 115 (36), 100 (66), 74 (48), 58 (31), 44 (29).

Example 4 Synthesis of 8-methylsulfanyl-1-octanol (FIG. 2, Scheme 2)

A 2.5 M BuLi solution (4 ml, 10 mmol) in hexane was added at −78° C. under stirring to 8-mercapto-1-octanol (4) (0.84 g, 4.76 mmol) (Narchem Corp., Chicago Ill.) dissolved in a 4:1 mixture of THF/HMPA. After 30 min, iodomethane (0.6 ml, 10 mmol) was added in one portion. The reaction mixture was allowed to warm to room temperature, quenched with water, and extracted with ether (2×30 ml). Ethereal extracts were washed with a saturated aq. NaCl solution, dried over anh. MgSO₄, and concentrated. Purification by flash chromatography afforded 0.65 g of known 8-methylsulfanyl-1-octanol (5) (Bennett & Gudgeon 1938; Kawabato et al. 1989) (>99% pure by GC, 78% yield).

Other 8-alkylsulfanyl-1-octanols, including 8-methylsulfanyloctan-1-ol, 8-ethylsulfanyloctan-1-ol (compound previously known; Hu & Neckers, 1997), 8-propylsulfanyloctan-1-ol, 8-butylsulfanyloctan-1-ol and 8-pentylsulfanyloctan-1-ol were furnished in similar ways.

Example 5 Synthesis of 8-propylsulfanyl-1-octanol (FIG. 2, Scheme 3)

8-Propylsulfanyl-1-octanol (7) was produced via hydrogenation of 8-allylsulfanyl-1-octanol (6) (Gries et al. 2008) in hexanes with 5% Pd/C as a catalyst (quantitative yield).

Example 6 Deterrence of Five 8-alkylsulfanyloctan-1-ols Against Aedes aegypti

To determine the deterrence of 8-allylsulfanyloctan-1-ols against Aedes aegypti, a 10% formulation of either 8-methylsulfanyloctan-1-ol, 8-ethylsulfanyloctan-1-ol, 8-propylsulfanyloctan-1-ol, 8-butylsulfanyloctan-1-ol, or 8-pentylsulfanyloctan-1-ol in mineral oil was applied in Experiments 1-5 at a dose of 1.5 mg (total composition) per cm² to the skin of the test person, and was bioassayed according to the protocol described under EXAMPLE 2. In Experiment 6, a 10% formulation of 8-allylsulfanyl-1-octanol (Gries et al. 2008) in mineral oil was bioassayed for comparison. Each of Experiments 1-6 was replicated 3-4 times.

In Experiments 1-5, 10% formulations of the 8-alkylsulfanyl-octan-1-ols in mineral oil provided protection from bites by Aedes egypti for an average duration ranging between 11-154 minutes (FIG. 2). The duration of protection was inversely related to the length of the alkyl chain. In Experiment 6, a 10% formulation of previously reported 8-allylsulfanyl-1-octanol provided protection for an average duration of 123 minutes.

FIG. 2 shows the duration of protection of a 100 cm² area of an exposed human forearm from bites by Aedes aegypti caused by 10% formulations of either 8-methylsulfanyloctan-1-ol (experiment 1), 8-ethylsulfanyloctan-1-ol (experiment 2), 8-propylsulfanyloctan-1-ol (experiment 3), 8-butylsulfanyloctan-1-ol (experiment 4), 8-pentylsulfanyloctan-1-ol (experiment 5) or 8-allylsulfanyloctan-1-ol (experiment 6) in mineral oil applied to the skin at a dose of 1.5 mg per cm², as opposed to no protection provided by mineral oil alone.

Example 7 Deterrence of (N,N)-diethyl-8-allylsulfanyl-octanamide Against Aedes aegypti

To determine the deterrence of (N,N)-diethyl-8-allylsulfanyl-octanamide against Aedes aegypti, a 10% formulation of (N,N)-diethyl-8-allylsulfanyl-octanamide in mineral oil was applied in Experiment 7 at a dose of 1.5 mg (total composition) per cm² to the skin of the test person, and was bioassayed according to the protocol described under EXAMPLE 2. Experiment 7 was replicated 4 times.

In Experiment 7, a 10% formulation of (N,N)-diethyl-8-allylsulfanyl-octanamide in mineral oil provided protection from bites by Aedes egypti for an average duration of 156 min, which was slightly longer than the average duration of protection provided by 8-allylsulfanyl-1-octanol in Experiment 6.

FIG. 3 shows the duration of protection of a 100 cm² area of an exposed human forearm from bites by Aedes aegypti caused by 10% formulations of (N,N)-diethyl-8-allylsulfanyl-octanamide (experiment 7) or 8-allylsulfanyloctan-1-ol (experiment 6) in mineral oil applied to the skin at a dose of 1.5 mg per cm², as opposed to no protection provided by mineral oil alone.

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1. A method of repelling and deterring landing and feeding by blood feeding arthropods on an animal, comprising applying an effective amount of one or more compounds selected from the group consisting of 8-methylsulfanyloctan-1-ol, 8-ethylsulfanyloctan-1-ol, 8-propylsulfanyloctan-1-ol, 8-butylsulfanyloctan-1-ol, 8-pentylsulfanyloctan-l-ol, and (N,N)-diethyl-8-allylsulfanyl-octanamide wherein the one or more compounds is for application to the skin, clothing or environment of the animal.
 2. The method of claim 1, wherein improvement of the repellence and deterrence of landing and feeding by blood feeding arthropods on an animal is achieved by combining effective amounts of said one or more compounds with effective amounts of one or more additional compounds selected from the group consisting of: vanillin, 1,8-cineole, linalool, citronellal, citronellol, camphor, menthone, isomenthone, menthol, borneol, isomenthol, α-terpineol, cis- and trans-piperitol, nerol, neral, cinnamaldehyde, cumin aldehyde, geraniol, geranial, thymol, bornyl acetate, menthyl acetate, cumin alcohol, geranyl formate, geranyl acetate, caryophyllene, cis-cinnamyl acetate, N,N-diethyl-m-toluamide, p-menthane-3,8-diol, 2-undecanone, tetrahydronootkatone, 1,10-dihydronootkatone, callicarpenal, and intermedeol.
 3. The method of claim 2, wherein the blood feeding arthropods comprise ticks and mites in the Order Acari (also known as Acarina) and insects in the Orders Mallophaga, Anoplura, Siphonaptera, Hemiptera, and Diptera.
 4. The method of claim 3, wherein the blood feeding insects in the Order Diptera comprises the Family Culicidae which comprise species in the genera Aedes, Culex, Anopheles, Chagasia, Bironella, Culiseta, Ochlerotatus, Psorophora, Tocorhynchites, Mansonia and Coquilettidia.
 5. The method of claim 4, wherein the insects in the Family Culicidae are Aedes aegypti, Anopheles gambiae, and Culex quinquefasciatus.
 6. The method of claim 2, wherein the animal is a mammal, bird, reptile or amphibian.
 7. The method of claim 6, wherein the mammal is a human.
 8. The method of claim 2, wherein the environment of the animal comprises the outdoors, bedding, furniture, dwellings and vehicles.
 9. The method of claim 2, wherein an effective amount of said blood feeding arthropod repellent and deterrent compounds range from 1 nanogram to 100 milligrams per square centimeter of skin, clothing or an environmental substrate.
 10. The method of claim 2, wherein said blood feeding arthropod repellent and deterrent compounds are formulated in effective amount with suitable inert ingredients to form a liquid, gel, paste, soap, spray, aerosol or powder.
 11. A composition for repelling and deterring landing and feeding by blood feeding arthropods on an animal comprising an effective amount of one or more compounds selected from the group consisting of 8-methylsulfanyloctan-1-ol, 8-ethylsulfanyloctan-1-ol, 8-propylsulfanyloctan-1-ol, 8-butylsulfanyloctan-1-ol, 8-pentylsulfanyloctan-1-ol,and (N,N)-diethyl-8-allylsulfanyl-octanamide, and a suitable carrier, wherein the composition is for application to the skin, clothing or environment of the animal.
 12. The composition of claim 11, wherein improvement of the repellence and deterrence of landing and feeding by blood feeding arthropods on an animal is achieved by combining effective amounts of said one or more compounds with effective amounts of one or more additional compounds selected from the group consisting of: vanillin, 1,8-cineole, linalool, citronellal, citronellol, camphor, menthone, isomenthone, menthol, borneol, isomenthol, cα-terpineol, cis- and trans-piperitol, nerol, neral, cinnamaldehyde, cumin aldehyde, geraniol, geranial, thymol, bornyl acetate, menthyl acetate, cumin alcohol, geranyl formate, geranyl acetate, caryophyllene, cis-cinnamyl acetate, N,N-diethyl-m-toluamide, p-menthane-3,8-diol, 2-undecanone, tetrahydronootkatone, 1,10-dihydronootkatone, callicarpenal, and intermedeol.
 13. The composition of claim 12, wherein the blood feeding arthropods comprise ticks and mites in the Order Acari (also known as Acarina) and insects in the Orders Mallophaga, Anoplura, Siphonaptera, Hemiptera and Diptera.
 14. The composition of claim 13, wherein the blood feeding insects in the Order Diptera comprises the Family Culicidae which comprise species in the genera Aedes, Culex, Anopheles, Chagasia, Bironella, Culiseta, Ochlerotatus, Psorophora, Tocorhynchites, Mansonia and Coquilettidia.
 15. The composition of claim 14, wherein the insects in the Family Culicidae are Aedes aegypti, Anopheles gambiae, and Culex quinquefasciatus.
 16. The composition of claim 12, wherein the animal is a mammal, bird, reptile or amphibian.
 17. The composition of claim 12, wherein the mammal is a human.
 18. The composition of claim 12, wherein the environment of the animal comprises the outdoors, bedding, furniture, dwellings and vehicles.
 19. The composition of claim 12, wherein effective amounts of said blood feeding arthropod repellent and deterrent compounds range from 1 nanogram to 100 milligrams per square centimeter of skin, clothing or an environmental substrate.
 20. The composition of claim 12, wherein said blood feeding arthropod repellent and deterrent compounds are formulated in effective amount with suitable inert ingredients to Preliminary Amendment in response to May 2, 2011 Notification of Missing Requirements form a liquid, gel, paste, soap, spray, aerosol or powder for application to the skin, clothing or environment of an animal. 21-24. (canceled) 